enzyme inhibitor/kinase inhibitor/TRK inhibitor. LOXO-101 is a potent, oral, selective inhibitor of tropomyosin receptor kinase (TRK) signaling molecules. The TRK family (TRKA, TRKB, and TRKC) has been implicated in diverse tumor types such as lung cancer, head and neck cancer, melanoma, colorectal cancer, sarcoma, and breast cancer. LOXO-101 was built specifically to inhibit TRK and is currently being evaluated in a Phase 1 dose escalation trial for patients with advanced solid tumors. LOXO-101 was developed in collaboration with Array BioPharma.

The SCOUT clinical trial is a multicenter, open-label trial in pediatric patients with advanced solid or primary CNS tumors. In order to meet the criteria for enrollment, patients must be between one year of age and 21 years of age with a locally advanced or metastatic solid tumor or primary CNS tumor that has progressed, or was nonresponsive to available therapies, and for which no standard or available curative therapy exists. Patients as young as one month old are eligible for enrollment if they have a diagnosis of infantile/congenital fibrosarcoma, with a documented NTRK fusion that has progressed, or was nonresponsive to available therapies, and for whom no standard or available curative therapy exists. (NCT02637687)

Latest
news:

• On October 21, 2018, Loxo Oncology announced updated clinical data for larotrectinib, an investigational oral, selective, and CNS-active TRK inhibitor, in adult and pediatric patients with TRK fusion cancers. The update included approximately one year of additional follow-up for the 55 patients described in the larotrectinib New England Journal of Medicine

publication from February 2018 . In addition, the update included data for an additional 67 patients who were subsequently enrolled across the larotrectinib development program. As of a data cut-off date of July 30, 2018 , median duration of response (DOR) had not been reached in either dataset. These data have been presented at the European Society for Medical Oncology ( ESMO ) 2018 Congress .

The ESMO presentation included additional follow-up for the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancers treated across Loxo Oncology's Phase 1 adult trial, Phase 2 trial (NAVIGATE), and Phase 1/2 pediatric trial (SCOUT). These patients were the subject of the New England Journal of Medicine publication from February 2018 , and constitute the primary analysis population supporting larotrectinib's NDA filing. The presentation also included data for the 67 TRK fusion patients subsequently enrolled. Presented data were based on a July 30, 2018 data cut-off date, providing approximately one year of additional follow up for the primary analysis population.

The datasets adhered to the intent to treat (ITT) principle and included patients with RECIST-evaluable disease enrolled to the three clinical trials, regardless of prior therapy or tumor tissue diagnostic method used to establish their TRK fusion diagnosis. In the ESMO presentation, response evaluations were based on investigator assessment.

The 122-patient integrated dataset included both adult and pediatric patients, who ranged in age from one month to 80 years and carried 24 unique TRK fusion-positive tumor diagnoses. Tumor types included 10 distinct soft tissue sarcomas, salivary gland, infantile fibrosarcoma, thyroid, lung, melanoma, colon, gastrointestinal stromal tumor (GIST), breast, bone sarcoma, cholangiocarcinoma, carcinoma of unknown primary, congenital mesoblastic nephroma, appendiceal, and pancreas cancers.
In the primary dataset, the overall response rate (ORR) was 80% (44/55) (95% CI: 67-90%), with a 62% partial response rate and an 18% complete response rate. In the supplementary dataset, the ORR was 81% (44/54) (95% CI: 69-91%), with a 65% partial response rate and a 17% complete response rate. Across both datasets, the ORR was 81% (88/109) (95% CI: 72-88%), with a 63% partial response rate and 17% complete response rate. The ORR analyses for the supplementary and integrated datasets included nine patients with unconfirmed partial responses awaiting confirmatory response assessments, but did not include 13 patients who were awaiting an initial response assessment and continuing on study.

Median duration of response (DOR) had not been reached in either the primary dataset or supplementary dataset, with median follow-up of 17.6 months and 7.4 months, respectively. In the primary dataset, Kaplan-Meier landmark analyses improved since the July 2017 data cut-off date. At 6 months, 88% of responses were ongoing (83% based on the July 2017 data cut-off date). At 12 months, 75% of responses were ongoing (71% based on the July 2017 data cut-off date). Kaplan-Meier landmark analyses of the supplementary dataset were highly concordant with the primary dataset. At 6 months, 93% of responses were ongoing and at 12 months, 81% of responses were ongoing. Across the integrated dataset, as of the July 2018 data cut-off date, 84% of responding patients remained on treatment or had undergone surgery with curative intent. Of 8 TRK fusion patients treated in the Phase 1 trial, 6 remained in response and on therapy at 22, 30, 33, 34, 37, and 41 months of follow up. With median follow-up for progression-free survival (PFS) of 19.6 months in the primary dataset, median PFS had been reached, at 28.3 months (95% CI: 9.9 months - Not estimable). This estimate is not statistically stable due to a low number of progression events, as evidenced by the wide confidence interval.

The safety data presented at ESMO encompassed the entire larotrectinib safety database in cancer patients (n=207), which includes 70 patients without a TRK fusion diagnosis. Larotrectinib was well tolerated, with the majority of adverse events recorded as grade 1 or 2. No treatment-related grade 3 or 4 adverse events occurred in more than 5% of patients. Eleven patients (9%) required larotrectinib dose reductions. In all cases, patients whose doses were reduced maintained their best response at the lower dose. One patient (<1%) discontinued larotrectinib due to an adverse event.

• On December 4, 2017, Loxo Oncology announced updated clinical data from the SCOUT clinical trial. These datahave been presented at the American Association for Cancer Research (AACR) Special Conference on Pediatric Cancer Research in Atlanta . As of a July 17, 2017 data cut-off date, 24 pediatric patients were enrolled in the dose escalation portion of the Phase 1 trial, including 17 patients with TRK fusion cancers. TRK fusion patients carried primary diagnoses of infantile fibrosarcoma, thyroid cancer, and various soft tissue sarcomas.

TRK Fusion Patients (n=17)*

Patients without TRK Fusions (n=7)

Independent Review Committee Assessed Response

Investigator Assessed Response

Investigator Assessed Response

Overall Response Rate
(ORR = PR+CR)

93%
(95% CI: 68% - 100%)

93%
(95% CI: 68% - 100%)

0%

Partial Response (PR)

80%

67%**

0%

Complete Response (CR)

13%

27%

0%

Stable Disease

7%

7%

0%

Progressive Disease

0%

0%

100%

* 2 patients not evaluable due to having non-measurable disease at baseline.

** Includes 2 patients with unconfirmed partial responses as of July 17, 2017, which were subsequently confirmed.

Among the 17 patients with TRK fusion cancers, 94% either remain on drug or received surgery with curative intent; four patients have been followed greater than one year and 12 have been followed greater than six months. The larotrectinib adverse event profile is consistent with data previously presented publicly. The most common treatment-related adverse events at the Phase 2 dose included increased liver function tests, neutropenia, and nausea, all largely grade 1.

• On April 19, 2016, Loxo Oncology announced the publication of a manuscript in the online edition of the journal Pediatric Blood and Cancer describing a confirmed RECIST partial response in the first patient enrolled in the recently opened pediatric Phase 1 dose-escalation trial of LOXO-101. The manuscript was co-authored with Nemours Children's Hospital, Northwestern University and St. Jude Children's Research Hospital .
The peer-reviewed manuscript describes a 16-month old female patient with advanced infantile fibrosarcoma (IFS), a rare pediatric cancer. Genetic testing revealed an ETV6-NTRK3 fusion, which is frequently found in IFS. Following multiple unsuccessful surgeries and courses of chemotherapy, the patient was enrolled in the pediatric Phase 1 trial of LOXO-101, which employs a liquid formulation of the drug designed specifically for pediatric patients unable to swallow capsules. Her disease involved the neck, face, skull, mastoids and cervical vasculature. Throughout the first cycle of treatment with LOXO-101, the parents noted improved engagement and playfulness. At the end of cycle 1 (day 28), imaging of the brain and neck showed tumor regression of more than 90 percent from baseline. Repeat scans at the end of cycle 2 showed a continued decrease in tumor volume. During the preparation of the manuscript, the patient was in study cycle 5, with a RECIST confirmed partial response, and was beginning to achieve normal developmental milestones. The patient experienced no adverse events related to LOXO-101.

• On December 22, 2015, Loxo Oncology, announced the enrollment of the first patient in its Phase 1 trial of LOXO-101 in pediatric patients with advanced solid or primary central nervous system (CNS) tumors.
The Phase 1 clinical trial is a multicenter, open-label trial in pediatric patients with advanced solid or primary CNS tumors. Loxo Oncology plans to open as many as 15 clinical sites in the U.S. In the dose-escalation phase, LOXO 101 will be administered orally twice daily, with the initial starting dose level intended to match the pharmacokinetic exposures of the 100 mg twice daily dose that is currently being employed in the LOXO-101 Phase 2 basket trial in adult patients. The actual dose for each patient will depend on patient body size and age. The trial will also utilize a liquid formulation of LOXO-101 designed specifically for pediatric patients unable to swallow capsules. The primary endpoint of the trial is to explore the safety of LOXO-101. Secondary endpoints include the characterization of pharmacokinetic properties, the identification of the maximum tolerated dose and/or the Phase 2 dose, a description of antitumor activity, and a description of pain and health related quality of life impact. In order to meet the criteria for enrollment, patients must be between one year of age and 21 years of age with a locally advanced or metastatic solid tumor or primary CNS tumor that has progressed, or was nonresponsive to available therapies, and for which no standard or available curative therapy exists. Patients at least one month old are eligible for enrollment if they have a diagnosis of infantile/congenital fibrosarcoma, with a documented NTRK fusion that has progressed, or was nonresponsive to available therapies, and for whom no standard or available curative therapy exists.
Additional patient cohorts may be enrolled in an expansion phase of the Phase 1 trial to better characterize safety and efficacy in patients with specific abnormalities in the NTRK genes or proteins.

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